Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co., Inc., 1-1, Suzuki-Cho, Kawasaki, Kanagawa, 210-8681, Japan.
Sci Rep. 2023 Aug 3;13(1):12576. doi: 10.1038/s41598-023-38698-2.
Phosphorodiamidate morpholino oligonucleotides (PMOs) are a promising type of antisense oligonucleotides, but their challenging synthesis makes them difficult to access. This research presents an efficient synthetic approach for PMOs using the H-phosphonate approach. The use of phosphonium-type condensing reagents significantly reduced coupling times compared with the current synthetic approach. Furthermore, phosphonium-type condensing reagents facilitated the fragment condensation of PMO, synthesizing up to 8-mer containing all four nucleobases with remarkable coupling efficacy. This is the first report on the convergent synthesis of PMOs. This approach would facilitate the large-scale synthesis of PMOs and accelerate their popularity and accessibility as a next-generation therapy.
磷酰二胺吗啉代寡核苷酸（PMO）是一种很有前途的反义寡核苷酸类型，但它们的合成具有挑战性，因此难以获得。本研究提出了一种使用 H-膦酸酯方法合成 PMO 的有效方法。与当前的合成方法相比，使用鏻型缩合试剂可显著缩短偶联时间。此外，鏻型缩合试剂有利于 PMO 的片段缩合，以高偶联效率合成了最多 8 个碱基的全含四种碱基的寡核苷酸。这是关于 PMO 收敛合成的首次报道。该方法将促进 PMO 的大规模合成，并加速其作为下一代疗法的普及和可及性。
